Intranasal delivery of insulin and a nitric oxide synthase inhibitor in an experimental model of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder in which motor neurons may be targeted by oxidative and nitrergic stress without sufficient compensation by intrinsic support mechanisms. In this work, we addressed two key tenets of this hypothesis for the pathogenesis of ALS. Using superoxide dismutase (SOD) 1G93A mice, we studied the impact of reduction of nitrergic stress within the CNS with the use of a broad spectrum nitric oxide synthase (NOS) inhibitor, NG-nitro-l-arginine methyl ester. A separate cohort of SOD1G93A mice received direct insulin neurotrophic support, ligating receptors expressed upon motor neurons, to attempt protection against neuronal and functional motor dropout. For direct access, we used a novel form of intranasal delivery that provides peak concentration levels in the CNS within 1 h of delivery without systemic side effects at doses which previously rescued retrograde loss of motor axons after axotomy. To identify even minor impacts of these interventions on the outcome, we utilized an intensive program of serial behavioral and electrophysiological testing weekly, combined with endpoint quantitative morphometry and molecular analysis. This intensive evaluation enhanced our knowledge of the time course in SOD1G93A mice and impact of the SOD1G93A mutation upon motor neurons and their function. Neither intervention had even minimal impact upon slowing progression of disease in SOD1G93A mice. Our data argue against significant roles for nitrergic stress in promoting motor neuron loss and the importance of alternative neurotrophic support mechanisms that might support motor neurons and prevent disease progression in SOD1G93A mice.
Martinez
J A
JA
Department of Clinical Neurosciences and the Hotchkiss Brain Institute, Room 155, University of Calgary, 3330 Hospital Drive, Northwest, Calgary, Alberta, Canada T2N 4N1.
Francis
G J
GJ
Liu
W Q
WQ
Pradzinsky
N
N
Fine
J
J
Wilson
M
M
Hanson
L R
LR
Frey
W H
WH
Zochodne
D
D
Gordon
T
T
Toth
C
C
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000281:Administration, Intranasal; D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000008:administration & dosage*; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage*; D009431:Neural Conduction / Q000187:drug effects; D009469:Neuromuscular Junction / Q000187:drug effects / Q000473:pathology; D010525:Peripheral Nerves / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics
D004791:Enzyme Inhibitors; D007328:Insulin; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D019331:NG-Nitroarginine Methyl Ester